Yin Litian, He Zhongmei, Yi Bing, Xue Linyuan, Sun Jianxin
Center for Translational Medicine, Department of Medicine, Thomas Jefferson University, Philadelphia, PA, United States.
Key Laboratory for Cellular Physiology, Ministry of Education, Department of Physiology, Shanxi Medical University, Taiyuan, China.
Front Pharmacol. 2020 Nov 4;11:574068. doi: 10.3389/fphar.2020.574068. eCollection 2020.
Statins, or 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors, have been widely used to lower cholesterol and prevent cardiovascular diseases. Recent preclinical and clinical studies have shown that statins exert beneficial effects in the management of breast cancer, while the underlying mechanisms remain to be elucidated. Herein, we sought to investigate the effect of statins on the expression of pituitary tumor-transforming gene 1 (PTTG1), a critical gene involved in human breast cancer invasion and metastasis. Our results showed that PTTG1 is highly expressed in malignant Hs578T and MDA-MB-231 breast cancer cell lines as compared with normal or less malignant breast cancer cells. Furthermore, we found that the expression of PTTG1 was markedly suppressed by lipophilic statins, such as simvastatin, fluvastatin, mevastatin, and lovastatin, but not by hydrophilic pravastatin. In a dose and time dependent manner, simvastatin suppressed PTTG1 expression by decreasing PTTG1 mRNA stability in MDA-MB-231 cells. Both siRNA-mediated knockdown of PTTG1 expression and simvastatin treatment markedly inhibited MDA-MB-231 cell invasion, MMP-2 and MMP-9 activity, and the expression of PTTG1 downstream target genes, while ectopic expression of PTTG1 promoted cancer cell invasion, and partly reversed simvastatin-mediated inhibition of cell invasion. Mechanistically, we found that inhibition of PTTG1 expression by simvastatin was reversed by geranylgeranyl pyrophosphate, but not by farnesyl pyrophosphate, suggesting the involvement of geranylgeranyl synthesis in regulating PTTG1 expression. Our results identified statins as novel inhibitors of PTTG1 expression in breast cancer cells and provide mechanistic insights into how simvastatin prevent breast cancer metastasis as observed in recent preclinical and clinical studies.
他汀类药物，即3-羟基-3-甲基戊二酰辅酶A还原酶抑制剂，已被广泛用于降低胆固醇和预防心血管疾病。最近的临床前和临床研究表明，他汀类药物在乳腺癌治疗中发挥有益作用，但其潜在机制仍有待阐明。在此，我们试图研究他汀类药物对垂体肿瘤转化基因1（PTTG1）表达的影响，PTTG1是一种参与人类乳腺癌侵袭和转移的关键基因。我们的结果表明，与正常或恶性程度较低的乳腺癌细胞相比，PTTG1在恶性的Hs578T和MDA-MB-231乳腺癌细胞系中高表达。此外，我们发现亲脂性他汀类药物，如辛伐他汀、氟伐他汀、美伐他汀和洛伐他汀，可显著抑制PTTG1的表达，但亲水性普伐他汀则无此作用。辛伐他汀以剂量和时间依赖性方式通过降低MDA-MB-231细胞中PTTG1 mRNA的稳定性来抑制PTTG1表达。PTTG1表达的siRNA介导的敲低和辛伐他汀处理均显著抑制MDA-MB-231细胞侵袭、MMP-2和MMP-9活性以及PTTG1下游靶基因的表达，而PTTG1的异位表达促进癌细胞侵袭，并部分逆转辛伐他汀介导的细胞侵袭抑制。机制上，我们发现香叶基香叶基焦磷酸可逆转辛伐他汀对PTTG1表达的抑制，但法尼基焦磷酸则不能，这表明香叶基香叶基合成参与调节PTTG1表达。我们的结果确定他汀类药物是乳腺癌细胞中PTTG1表达的新型抑制剂，并为辛伐他汀如何预防乳腺癌转移提供了机制性见解，这在最近的临床前和临床研究中已得到观察。
